Compounds which interact with the thyroid hormone receptor for the treatment of fibrotic disease

ABSTRACT

A method of alleviating a fibrotic disease selected from lung fibrosis and liver cirrhosis in a warm blooded animal, which comprises administering an effective amount of at least one compound having the formula (I)  
                 
 
     in which X stands for the oxygen or sulphur atom or for the imino (—NH—) or sulphonyl (—SO 2 —) radical, Y stands for a direct linkage, or for the oxygen or sulphur atom or for the sulphonyl (—SO 2 —) radical or for the radical of the formula —CR 1 R 2 —, wherein R 1  and R 2  which may be the same or different are hydrogen, alkyl or aryl radicals or R 1  and R 2  may be joined together to form a cycloalkyl ring, n is an integer having the value 0 or 1, provided that when n is 0, Y stands for the oxygen or sulphur atom or for the sulphonyl (—SO 2 —) radical, or an ester, amide or salt thereof.

[0001] This invention relates to fibrotic diseases.

[0002] There are many fibrotic diseases in the human. These aresometimes referred to as chronic connective tissue diseases, and includedegradative and proliferative conditions. They include, for example,deterioration of the joints in arthritis, deformation of vessel walls inartherosclerosis, accelerated cardiovascular problems associated withdiabetes, lung fibrosis and cirrhosis of the liver. These fibroticdiseases are generally considered and studied as separate and differentproblems However, it is possible that common pathways exist in all thesefibrotic diseases Indeed, corticosteriods are used in the treatment ofmany of these diseases to relieve symptoms and prevent associated tissuedestruction and scarring; however, the use of corticosteroids isassociated with dose and treatment duration side-effects which limit theusefulness of this type of compound.

[0003] Some fibrotic diseases are particularly distressing, such as, forexample, those involving deterioration of cartilage and bone in thejoint. Amelioration of such diseases is a particularly difficult targetfor the pharmaceutical industry. These conditions are often accompaniedby distressing levels of pain and gradual impairment of structural bodyfunction and movement. An added difficulty in attempting to find asatisfactory cure or improvement is that joint disease appears to belargely species specific. Therefore, research into joint disease in manis made more difficult in that animal models may not be appropriate.

[0004] In mankind, joint disease is generally progressive and affectsall ages, but is particularly prevalent in middle and old age. Qualityof life of the patient is severely reduced as the level of pain andreduction in mobility increase. Treatments hitherto have, therefore,been directed at manifestations of the disease or malfunction which arecomparatively less difficult to treat. In rheumatoid arthritis, theseinclude symptom-modifying anti-rheumatic drugs (so-called SMARD) for therelief of pain and decrease in inflammation at the joint or in thesynovial membrane, such as, for example, non-steroidal anti-inflammatorydrugs (so-called NSAID). Some drugs are said to be disease modifying(so-called DMARD), such as, for example, non-cytotoxics such asanti-malarials, gold, sulphasalazine, D-penicillamine, and cytotoxicssuch as cyclophosphamide and chlorambucil. However, such drug treatmentsare often associated with unpleasant or undesirable side effects, whichlimit their application and utility. A new category of anti-rheumaticdrugs, Disease Controlling Anti-Rheumatic Drugs, (so-called DCARD) hasbeen proposed to describe drugs that effectively control the destructiveprocesses but as yet no marketed anti-rheumatic drugs merit thisclassification, although corticosteroids have some inhibitory effect onthe articular damage at the low doses that can be tolerated for longterm treatment

[0005] However, consideration of the above fibrotic diseases as a classhaving a common pathway may prove valuable in attempting to invent newtreatments

[0006] It is known that corticosteriods can regulate gene transcriptionby binding to their specific receptor which is one member of the steroidreceptor super-family (Physiology of the steroid-thyroid hormone nuclearreceptor superfamily Williams G R, Franklyn J A. Bailliére's ClinicalEndocrinology and Metabolism Vol 8 No 2 pp241-266 1994). Thissuper-family includes the glucocorticoid, oestrogen, progesterone,androgen, thyroid hormone, Vitamin D and retinoic acid receptors. Suchreceptors are responsible for the regulation of many genes includingthose encoding tissue destructive proteolytic enzymes, for example,metalloproteinases (sometimes referred to as MMPs) One such MMP iscollagenase 1. Corticosteroids interact specifically with the corticoidreceptor which then binds to the promoters of the genes This ligandedcorticosteroid receptor represses activation of the collagenase gene bymodulating the activity of transcription factor AP-1 (activating protein1, heterodimer of c-fos and c-jun proteins; reviewed by Cato and WadeBioEssays Vol 18 No 5 pp371-378 1996). The liganded steroid receptorthus modulates production of protein destructive enzymes, therebyreducing degradation of joint tissues such as cartilage and bone.

[0007] Many of the members of the superfamily of steroid receptors canmodulate tissue destructive proteolytic enzyme production when ligandedwith the natural hormone. However, use of the natural hormone atpharmacological levels is associated with severe side effects due totheir biological activity in many physiological systems. Corticosteroidseffectively inhibit proteolytic enzyme production at the transcriptionallevel, through modulation of AP1, but the problem with corticosteroidsis that they have additional transactivation effects on genes that leadto side effects, such as bone osteoporosis, diminishment of the immuneresponse and water retention Some of these side effects can be lifethreatening. Therefore, such inhibition or modulation in the substantialabsence of the above hitherto undesirable associated side effects wouldrepresent a major therapeutic advance.

[0008] These undesirable additional transactivation effects aresurprisingly substantially avoided in accordance with the presentinvention. It has been found that the use of the compounds describedbelow have substantially no transactivation properties and do nottransrepress body defence mechanisms signalled by immune hormones suchas the cytokines, IL1 and TNF and the early response transcriptionfactor NFκB (Mukaida N et al, J Biol Chem, 269, 13289-13295, 1994). Thecompounds below, and their associated pharmaceutical compositions, arenot likely, therefore, to compromise the immune system, which is one ofthe one of the major problems associated with the use ofcorticosteroids. This is a surprising finding and clearly separates thisclass of molecule from the conventional steroid hormones.

[0009] It has been found that compounds (I) hereinafter described areable to regulate MMP gene activation, but surprisingly not throughoccupation of either the corticosteroid receptor or the androgenreceptor. Therefore, surprisingly compounds (I) appear to regulate MMPgene activation through a different receptor and hence compounds (I) canthereby substantially prevent transcription of MMP, includingcollagenase 1.

[0010] Indeed, it has been further found that compounds (I) acts throughoccupation of the thyroid hormone receptor. Herein lies the basis of thepresent invention.

[0011] Thus according to the present invention, a method is provided ofalleviating fibrotic disease by regulating tissue destructiveproteolytic enzyme production in the presence of thyroid receptorbinding, but in the substantial absence of substantive corticosteroidand androgen receptor binding. This is effected by administration of aneffective amount of at least one compound having the formula (I)

[0012] in which X stands for the oxygen or sulphur atom or for the imino(—NH—) or sulphonyl (—SO₂—) radical, Y stands for a direct linkage, orfor the oxygen or sulphur atom or for the sulphonyl (—SO₂—) radical orfor the radical of the formula —CR¹R²—, wherein R¹ and R² which may bethe same or different are hydrogen, alkyl or aryl radicals ashereinafter described, ring B may be optionally substituted by one ormore substituents selected from halogen atoms and alkyl and arylradicals, n is an integer having the value 0 or 1, and esters, amidesand salts thereof

[0013] In the compounds having the formula (I), R¹ and R² may be thesame or different and preferably R¹ is selected from hydrogen or 1-4Calkyl, and R² from hydrogen, 1-4C alkyl or phenyl (which may beoptionally substituted with at least one halogen atom, for example,chlorine, bromine), and R¹ and R² may be joined together to form acycloalkyl ring (for example, cyclohexyl), the ring B may be optionallycontain one or more substituents selected from halogen atoms and 1-4Calkyl. Most preferably, the 1-4C alkyl radicals are methyl or ethyl, andthe halogen atom is chlorine.

[0014] Esters of compound (1) may be useful in the present invention.Such esters are preferably derived from alcohols having the formulaR³—OH, where R³ is preferably 1-4C alkyl, most preferably methyl orethyl. Salts of compound (I) include alkali metal and alkaline earthsalts, and include magnesium, aluminium, bismuth, ammonium, andpreferably sodium, potassium and calcium. Where the compound (I)contains a strongly basic substituent, acid addition salts thereof, suchas the hydrochloride, are comprehended.

[0015] Compounds having the formula (I), in which n is 1, and R¹ and R²which may be the same or different are hydrogen or alkyl radicals, aredescribed in United Kingdom patent specification 1140748, the disclosureof which is incorporated herein. Such compounds are considered to beuseful in the treatment or prophylaxis in humans and animals of suchdiseases as coronary artery disease and atherosclerosis. This is becausethey are said to reduce the concentration of cholesterol and/ortriglycerides in the blood serum and the level of fibrinogen in bloodplasma of rats They are also said to possess anti-inflammatory activityin rats, and are, therefore, considered to be useful in the treatment ofinflammatory signs and symptoms such as rheumatoid arthritis in man;further work has shown that such compounds have substantially noanti-inflammatory properties (Billingham M E J and Rushton A,Anti-inflammatory and Anti-arthritic Drugs, Vol III, Edited by. K DRainsford, 31-63, 1985, CRC Press)). A particularly preferred compound,1-[4-(4-chlorophenyl)benzyloxy]-1-methylpropionic acid, has the formula(II)

[0016] European patent specification 0 037 698, the disclosure of whichis incorporated herein, describes processes for the production ofcompounds having the formula (I) in which n takes the value 1, Y is adirect link and R¹ and R² which may be the same or different arehydrogen or (1-4C) alkyl. A preferred compound has the formula (III).

[0017] United Kingdom patent specification 860303, the disclosure ofwhich is incorporated herein, describes compounds having the formula (I)in which n takes the value 0. A preferred compound has the formula (IV)and is known as clofibrate.

[0018] According to the present invention a method of modifying fibroticdisease in warm blooded animals is provided which comprisesadministering the animal an effective amount of at least one compoundhaving the formula (I). In a further embodiment of the present inventiona pharmaceutical composition is provided containing at least onecompound having the formula (I) for the structural modification offibrotic tissue in a warm blooded animal.

[0019] In accordance with the present invention, many fibrotic andproliferative conditions are considered to gain benefit from treatmentwith the pharmaceutical composition These include, for example,rheumatoid arthritis, psoriatic arthritis and psoriasis itself, theloosening of prosthetic joints, atherosclerosis of cardiac and coronaryvessels and large arteries, the complications of diabetes, lungfibrosis, liver cirrhosis, systemic sclerosis, muscular dystrophy.

[0020] In order to be useful in the treatment of the above conditions inaccordance with the present invention, the above compounds may beadministered as a pharmaceutical composition by any suitable route, butpreferably orally, as, for example, tablets, capsules, suspension,emulsions, powders, syrups, elixirs. They may be administered assuppositories. The pharmaceutical compositions may be formulated toinclude any pharmaceutically acceptable excipient and may be prepared byany suitable method known on the art, such as those described in any ofthe above patent specifications. The compositions should preferably beadministered to ensure that the patient receives between 0.01 g and 0.5g of active ingredient per day; the composition containing suitablybetween 0.01 g and 0.5 g of active ingredient.

[0021] The invention is illustrated with reference to the followingexperimental information

[0022] Two plasmid constructs were introduced by standard calciumphosphate precipitation of DNA followed by glycerol shock (Ausubel F M,Brent R, Kingston D D, Moore J G et al Current protocols in molecularbiology 1994 Greene Publishing Associates/Wiley-Interscience, New York,N.Y.) using a transformed African Green Monkey kidney cell line (CV1)(Schneikert J, Peterziel H, Defossez P- A, Klocker H, de Launoit Y andCato ACB Androgen receptor-Ets protein interaction is a novel mechanismfor steroid hormone-mediated down-modulation of matrix metalloproteinaseexpression. Journal of Biological Chemistry. Vol 271(39) (pp23907-23913), 1996).

EXPERIMENT 1

[0023] This experiment was intended to show reduction in MMP promoteractivity. Accordingly, the following two plasmids were included into CV1cells described above

[0024] (a) Either of GR1 or pSG5ARF containing glucocorticoid orandrogen receptor (AR) respectively, both at 2 μg per 5×10⁵ cells,driven by the Rous sarcoma virus promoter, and

[0025] (b) a plasmid containing the −73/+63 portion of the collagenase 1promoter linked to luciferase gene at 8 μg per 5×10⁵ cells.

[0026] These cells were stimulated using TPA(12-O-tetradecanoylphorbol-13-acetate) at 75 ng/ml, which enhanced theactivity of the collagenase promoter. The stimulation increasedluciferase production, which was measured by luminescence after additionof the luciferase substrate (luciferin) and co-factors.

[0027] The blank represented the inclusion of these two plasmids alonewith little endogenous activation of collagenase. Addition of TPAstimulated the activity of this promoter region, resulting in a highlevel of luciferase production which is eventually seen as anenhancement in fluorescence (Y-axis). Both dihydroxytestosterone (DHT)at 10⁻⁷M and dexamethazone (Dex) at 10⁻⁷M were able to down regulatethis activation through their respective receptors. CPII was compound IIabove, clobuzarit. “Empty” indicated the results when neither GR1 or ARreceptors were present. The results are presented in Table 1. TABLE 1Empty GR1 AR Raw % Raw % Raw % counts control counts control countscontrol Blank 2399 100 12842 100 2668 100 CPII 1882 78 6151 48 1374 51TPA 5407 225 57519 448 11639 436 TPA + CPII 2747 115 39968 311 5986 224TPA + DHT 3711 139 TPA + Dex 10981 86

[0028] The above results are presented graphically in FIGS. 1a and 1 b.From the results in Table 1, it is shown that Compound II was also, inaddition to DHT or Dex, able to down regulate collagenase I activation,and also to inhibit partially the background level of collagenasepromoter activity. The level of this reduction which is achieved by theuse of Compound II in both stimulated and unstimulated conditions issimilar, when expressed as ratio of luciferase counts seen withoutinclusion of this molecule, over observable counts when Compound II isincluded. This suggests that Compound II does not require the presenceof either receptor in order to exert its action. This is furthersupported by the observation that Compound II is able to reduce thelevel of both TPA stimulated and unstimulated collagenase I (MMP)promoter activity in the absence of either receptor (Empty).

EXPERIMENT 2

[0029] This experiment was intended to investigate the activation ofandrogen and corticosteroid receptors by compound I

[0030] The CV1 cells described above were transfected with the followingtwo plasmids

[0031] (a) PGL3MMTV plasmid, containing a transcription site which isactivated by the androgen and glucocorticoid receptor, linked to theluciferase gene at 9 μg per 5×10⁵ cells, and

[0032] (b) either one of the plasmids GR1 or pSG5ARFin, containingglucocorticoid or androgen receptor (AR) respectively, under the controlof constitutively active promoters, both at 2 μg per 5×10⁵ cells.

[0033] The blank represented the inclusion of these two plasmids alone,resulting in the absence of receptor activity. Inclusion ofdihydroxytestosterone (DHT) at 10⁻⁷M or dexamethazone (Dex) at 10⁻⁷M tothe culture medium enabled the receptor to stimulate the transcriptionof the promoter region linked to luciferase which was eventually seen asan enhancement in fluorescence (Y-axis). CPII was compound II above,clobuzarit, which was used at 10⁻⁷M. TABLE 2 Raw counts % control ARBlank 4637 100 DHT 1731765 37347 CPII 33130 714 DHT + CPII 1232241 26574GR1 Blank 3569 100 Dex 619085 17346 CPII 3272 92 Dex + CPII 748249 20965

[0034] The above results are presented graphically in FIGS. 2a and 2b.From the results in Table 2, it is shown that Compound II showsnegligible activity to activate the same mechanism as that produced bythe addition of the two steroids DHT and Dex.

EXPERIMENT 3

[0035] This experiment was intended to show the effect of compounds I ona mediator of the immune response, nuclear factor −κB (NF−κB).

[0036] The following two plasmids were included into CV1 cells describedabove

[0037] (a) GR1 as described above at 2 μg per 5×10⁵ cells, and

[0038] (b) a plasmid designated 3-EnhTK-Luc (at 0.5 μg per 5×10⁵ cells)which contains a transcription site that is activated by NFκB. The cellsthemselves are capable of synthesising this protein and hence it is notnecessary to transfect this as well. The blank represented the inclusionof these two plasmids alone; the relatively high value was caused by (i)the high level of serum in the culture, and (ii) the associated stressthat the cells underwent during the transcription process—both of whichupregulate NFκB. There was also a related relatively low activation ofTNF (at 4 ng/ml) above a serum containing blank in the experiment. TNFwas tumour necrosis factor alpha. TABLE 3 Raw counts % control Blank59538 100 CPII 75812 127 TNF 82579 139 TNF + CPII 135886 228 TNF + Dex18525 31

[0039] The above results are presented in FIG. 3. The results show thatCompound II shows little variation from the background value, indicatingthat it is not able to upregulate transcriptional activity by NFκB. Thelack of inhibitory effect of Compound II on NFκB transcription is incontrast to the marked effect of Dex, showing that Compound II does notact as an anti-inflammatory agent, so supporting the earlier clinicaldata. Also, from the lack of substantive stimulation, it can also beinferred that Compound II, in contrast to DEX, does not interfere withimmune response signalling.

EXPERIMENT 4

[0040] These experiments were intended to identify the receptor throughwhich compounds I might be acting to block collagenase promoteractivity.

[0041] Transfection procedure hereinbefore described with CV1 cells wasrepeated using MCF-7 mammary breast cancer cells derived from pleuraleffusion from a breast cancer patient Additionally, each experimentincluded transfection of a plasmid (at 8 μg per 5×10⁵ cells) containingthe −517/+63 section of the collagenase (MMP-1) promoter linked to theluciferase gene. TPA was used as above to stimulate activity of thecollagenase promoter resulting in luciferase production. Compound II or3,3,5-triiodo-L-thyronine (T3) was included (both at 10⁻⁸M), the latterbeing a known ligand for the thyroid hormone receptor.

[0042] A series of three experiments was then carried out.

[0043] Experiment 4.1. As MCF-7 cells express endogenous thyroid hormonereceptors, only the collagenase promoter plasmid (at 8 μg per 53 10⁵cells) was transfected into the MCF-7 cells. The results are shown inTable 4.1. TABLE 4.1 Raw Counts % Control Blank 12575 100 CPII 6029 47.9TPA 147665 1174.3 TPA + T3 428062 3404.1 TPA + CPII 352376 2802.2

[0044] The results in Table 4.1, presented graphically in FIG. 4.1, showthat in MCF-7 cells, both thyroid hormone and Compound II are ablefurther to enhance TPA stimulation of luciferase production

[0045] Experiment 4.2. The procedure of Experiment 4.1 was repeatedexcept that a second plasmid, containing 662 bp antisense construct forthe thyroid receptor (at 8 μg per 5×10⁵ cells) was additionallytransfected. The results are shown in Table 4.2. TABLE 4.2 Raw Counts %Control Blank 1458 100 CPII 2379 163.2 TPA 4975 341.2 TPA + T3 199111365.6 TPA + CPII 8716 597.8

[0046] The results in Table 4.2, presented graphically in FIG. 4.2, showthat when the thyroid hormone receptor synthesis is inhibited,luciferase production via the action of T3 and compound II issubstantially prevented.

[0047] Experiment 4.3. A second plasmid was introduced containing pSP71vector (Promega) (at 2 μg per 5×10⁵ cells) containing the codingsequence for the chick thyroid hormone receptor which shows highhomology to the human thyroid hormone receptor, driven by the Roussarcoma virus promoter to ensure constitutive production. The resultsare shown in Table 4.3 TABLE 4.3 Raw Counts % Control Blank 2183 100CPII 1572 72 TPA 11528 528 TPA + T3 1604 73 TPA + CPII 4414 202

[0048] The results in Table 4.3, presented graphically in FIG. 4.3, showthat Compound II, as well as thyroid hormone, is able to reducestimulated collagenase transcription

[0049] Taken together, the results of Experiments 4.1, 4.2 and 4.3 showthat compound II mimics the action of T3 which is a known ligand for thethyroid hormone receptor.

EXPERIMENT 5

[0050] This experiment was designed to demonstrate down-regulation ofpro-MMP-1 and phosphorylation at serine 73 of c-jun, the latter of whichis one half of the protein dimer AP-1, a key regulator ofmetalloprotease expression.

[0051] Methods

[0052] Rheumatoid fibroblasts were cultured from synovium obtained fromthe knee joint of a patient with rheumatoid arthritis. Cells werecultured in monolayer with DMEM tissue culture medium (Gibco) with theinclusion of 5% v/v charcoal stripped serum in 75 cm² flasks. The cellswere treated for 36 hours with the addition of 10 ng/ml TPA (phorbolester) plus 5×10⁻⁷M thyroid hormone, Compound II or Compound III. TPAand drugs were added at time zero and at 30 hours, the TPA additionensured phosphorylation of c-jun.

[0053] After 36 hours, cells were lysed in phosphate buffered saline(PBS) containing protease inhibitors and 0.1% Triton-X-100, and thenboiled for 5 minutes in non-reducing gel loading buffer. Samples of celllysate corresponding to equal cell number were loaded onto a 12.5% SDSpolyacrylamide gel, and electrophoresis using a Bio-Rad™, (Bio-RadLaboratories, California USA) Mini Protean II cell was performed atapproximately 100V for one hour.

[0054] Transfer of proteins to nitrocellulose membrane was performedusing a Bio-Rad Mini Trans-Blot transfer cell.

[0055] Immunoblotting was performed using polyclonal rabbit anti-humanphosphorylation specific (ser 73) c-jun (cat. No 06659, UpstateBiotechnology), or MMP-1 (cat. No. RDI-MMP1Habr, Research Diagnostics)antibodies diluted 1:1000 in Tris buffered saline+3% fat free milkpowder. Swine anti-rabbit horseradish peroxidase conjugated antibody,(cat. No. p0217, Dako) also at 1:1000 dilution was used as the secondaryantibody. Chemiluminescent detection was employed using Amershamreagents according to manufacturer's instructions. Visualisation wasachieved by exposing the membrane to X-ray film (Kodak) for one hour.

[0056] Results are shown in FIG. 5. Left side column of the figure showsbands corresponding to phosphorylated c-jun (at serine 73), complexedwith DNA, at the top of the figure. Right hand side column demonstratesa strong regulated band corresponding to pro-MMP-1 and a faint band at alower molecular weight corresponding to active-MMP-1 Lanes 1 and 5 cellstreated with TPA alone; Lanes 2 and 6 cells treated with TPA plusthyroid hormone; Lanes 3 and 7 cells treated with TPA plus Compound II,Lanes 4 and 8 cells treated with TPA plus Compound III.

[0057] Lanes 2, 3 and 4 show a lower intensity and therefore, amount ofphosphorylation of c-jun, when compared to the TPA alone treated controlin lane 1 Similarly, lanes 6, 7 and 8 show a lower intensity andtherefore, a lower amount of pro-MMP-1, when compared to the TPA alonetreated control in lane 5. Since the lower molecular weight band acrosslanes 5, 6, 7 and 8 corresponding to active MMP-1 is very faint, theregulation by thyroid hormone, and Compounds II and III appears to beoccurring at the transcriptional level to produce a similar effect tothryoid hormone on the expression of pro-MMP-1.

[0058] Summary

[0059] Compound II, typical of compounds I, demonstrated steroid likeproperties in its ability to reduce collagenase promoter activity,although this was evident in the substantive absence of glucocorticoidor androgen receptors. Additionally, compound II did not activate aconstruct designed to show responsiveness to the glucocorticoidreceptor. It did not enhance or block the activity of an immune systemmediator, demonstrating that it does not possess anti-inflammatoryproperties, neither does it compromise immune response signalling. In afurther experiment, the activity of compound II was identical to T3 inthe absence and presence of endogenous or transfected thyroid hormonereceptor. This demonstrated a common mechanism for these two molecules.The liganded thyroid hormone receptor is known to be able to downregulate collagenase promoter activity (A novel mechanism of action forv-ErbA: abrogation of the inactivation of transcription factor AP-1 byretinoic acid and thyroid hormone receptors, Desbois-C; Aubert-D;Legrand-C; Pain-B; Samarut-J Cell. Nov. 15, 1991; 67(4): 731-40),although the mechanism by which this occurs has not yet been elucidated.

1. A method of alleviating fibrotic disease by regulating tissuedestructive proteolytic enzyme production in the presence of thyroidreceptor binding but in the substantial absence of substantivecorticosteroid and androgen receptor binding.
 2. A method as claimed inclaim 1 in which the fibrotic disease is regulated by administration ofan effective amount of at least one compound having the formula (I)

in which X stands for the oxygen or sulphur atom or for the imino (—NH—)or sulphonyl (—SO₂—) radical, Y stands for a direct linkage, or for theoxygen or sulphur atom or for the sulphonyl (—SO₂—) radical or for theradical of the formula —CR¹R²—, wherein R¹ and R² which may be the sameor different are hydrogen, alkyl or aryl radicals as hereinafterdescribed, ring B may be optionally substituted by one or moresubstituents selected from halogen atoms and alkyl and aryl radicals, nis an integer having the value 0 or 1, and esters, amides and saltsthereof.
 3. A method as claimed in claim 1 in which the fibrotic diseaseis regulated by administration of an effective amount of at least onecompound having the formula (II)


4. A method as claimed in claim 1 in which the fibrotic disease isregulated by administration of an effective amount of at least onecompound having the formula (III)


5. A method of regulating gene activation in the substantial absence ofoccupation of either corticosteroid receptor or androgen receptor.
 6. Amethod of regulating MMP gene activation in by the occupation of thyroidreceptor.
 7. A method of regulating MMP gene activation by theoccupation of thyroid receptor but in the substantial absence ofoccupation of either corticosteroid receptor or androgen receptor.
 8. Amethod of regulating MMP gene activation by the occupation of thyroidreceptor but in the substantial absence of occupation of eithercorticosteroid receptor or androgen receptor by administration of aneffective amount of at least one compound having the formula (I)
 9. Theuse of a compound having the structure (I) in the preparation of amedicament for the structural modification of fibrotic tissue in a warmblooded animal by regulating tissue destructive proteolytic enzymeproduction in the presence of thyroid receptor binding but in thesubstantial absence of substantive corticosteroid and androgen receptorbinding.

in which X stands for the oxygen or sulphur atom or for the imino (—NH—)or sulphonyl (—SO₂—) radical, Y stands for a direct linkage, or for theoxygen or sulphur atom or for the sulphonyl (—SO₂—) radical or for theradical of the formula —CR¹R²—, wherein R¹ and R² which may be the sameor different are hydrogen, alkyl or aryl radicals as hereinafterdescribed, ring B may be optionally substituted by one or moresubstituents selected from halogen atoms and alkyl and aryl radicals, nis an integer having the value 0 or 1, and esters, amides and saltsthereof.
 10. The use as claimed in claim 4 in which the compound has theformula (II)


11. The use as claimed in claim 4 in which the compound has the formula(III)


12. The use of a compound having the formula (I) in the preparation of amedicament for the regulation of MMP gene activation in the substantialabsence of occupation of either corticosteroid receptor or androgenreceptor.
 13. The use of a compound having the formula (I) in thepreparation of a medicament for the regulation of MMP gene activation inby the occupation of thyroid receptor.
 14. The use of a compound havingthe formula (I) in the preparation of a medicament for the regulation ofMMP gene activation by the occupation of thyroid receptor but in thesubstantial absence of occupation of either corticosteroid receptor orandrogen receptor.